BMP-3 Signaling in the Formation and Regulation of Bone

描述（由申请人提供）：尽管在过去十年中对骨形态发生蛋白（BMPs）的研究呈指数级增长，但我们实际上对单个BMPs在骨骼中的生理作用知之甚少。我们决定集中研究BMP3在骨中的作用是基于几个重要的发现。首先，尽管BMP3是骨中最丰富的BMP，占骨基质中储存的BMP蛋白总量的65%，但对其生物学知之甚少。我们对BMP3感兴趣的第二个原因是，最近有报道称体内BMP3水平的变化与骨折愈合、骨骼的机械负荷以及内源性骨形成的丧失有关。最后，也许最有趣的是我们的观察，BMP3基因敲除小鼠显示出明确的骨骼表型，而骨骼模式没有改变。在5周龄时，BMP3基因敲除动物的骨小梁总骨量是其野生型窝鼠的两倍，表明BMP3是骨量的负调节因子。在体外，BMP3能够在强效成骨刺激下对成骨细胞分化发挥抑制作用。BMP3负性调节骨量的信号通路尚未确定。由于成骨bmp现已成为每年成千上万患者用于增强骨形成的治疗剂，因此了解BMP3如何发挥其对骨量的调节作用具有广泛的临床意义。在本研究中，我们将研究BMP3信号的缺失对骨骼形成、生长和维持的影响（SA1）；研究BMP3表达增加对骨骼形成、生长和维持的影响（SA2）；解剖BMP3信号通路（SA3），明确BMP3在骨膜和骨领骨形成调控中的功能（SA4）。我们相信，我们从实验计划中获得的信息将是理解单个bmp（单独或相互结合）如何在骨骼模式、骨形成和骨量维持中发挥作用的关键。

DESCRIPTION (provided by applicant): Although research on the bone morphogenetic proteins (BMPs) has expanded exponentially over the past decade, we actually know very little about the physiological roles that individual BMPs play in the skeleton. Our decision to focus this proposal on role the BMP3 in bone is based on several important findings. First, although BMP3 is the most abundant BMP in bone, accounting for 65% of the total BMP protein stored in bone matrix, little is known about its biology. A second reason for our interest in BMP3 are recent reports that correlate changes in BMP3 levels in vivo with fracture healing, mechanical loading of the skeleton, and the loss of endogenous bone formation with age. Finally, and perhaps most intriguing is our observation that BMP3 knockout mice display an unequivocal bone phenotype without a change in skeletal patterning. At five weeks of age, the total trabecular bone mass of BMP3 knockout animals is twice that of their wild-type littermates, demonstrating that BMP3 is a negative regulator of bone mass. In vitro, BMP3 is able to exert an inhibitory effect on osteoblast differentiation in the presence of potent osteogenic stimuli. The signaling pathway used by BMP3 to negatively regulate bone mass has not yet been identified. As osteogenic BMPs are now therapeutic agents used to augment bone formation in thousands of patients each year, understanding how BMP3 exerts its regulatory effects on bone mass has wide ranging clinical significance. In this proposal, we will: investigate what the lack of BMP3 signaling does to the formation, growth and maintenance of the skeleton (SA1); examine the effects of increased BMP3 expression on the formation, growth and maintenance of the skeleton (SA2); dissect the BMP3 signaling pathway (SA3), and define the function of BMP3 in regulating bone formation in the periosteum and bone collar (SA4). It is our belief that the information we obtain as a result of our experimental plan will be key to understanding how individual BMPs, alone and in combination with one another, function in skeletal patterning, bone formation, and the maintenance of bone mass.